Project Summary Epilepsy is a complex disorder which involves much more than seizures. It may also be accompanied by a range of associated comorbid health conditions with significant health and quality of life implications as emphasized by the National Academy of Science-sponsored Committee on the Public Health Dimensions of the Epilepsies.1 Our research laboratories have generated a rodent model of experimental febrile status epilepticus (eFSE), which provokes both temporal lobe epilepsy-like seizures and cognitive deficits, thereby providing a powerful tool to probe the mechanisms underlying these conditions. Following eFSE, rats exhibit significant deficits in the active avoidance test?a test of spatial cognition?and show altered hippocampal oscillatory activity and abnormal temporal coding of action potentials when compared with controls. Recently, we identified some of the mechanisms underlying epilepsy-promoting functional changes in the hippocampal network provoked by eFSE. Specifically, we observed coordinated transcriptionally-regulated changes in the expression of multiple genes governing neuronal behavior which resulted from eFSE-induced up-regulated expression and function of the neuron-restrictive silencing factor (NRSF). Remarkably, our preliminary studies indicate that both the cognitive deficits and the neuronal discoordination can be prevented by blocking NRSF following status epilepticus. While the therapeutic implications of our findings are exciting, it is not yet known how eFSE-induced abnormal NRSF activities contribute to disruption of gene expression and maturation of specific cell populations throughout the circuit affected by eFSE. This proposal aims to determine the biological underpinnings of eFSE-induced cognitive deficits at the molecular, single cell and circuit levels, and to establish how NRSF-blockade reverses these deficits. In addition, we will determine if NRSF is involved in memory problems associated with other developmental seizures as this will be a requisite for translation of our discoveries. The proposed multidisciplinary, multidimensional and cutting-edge experiments will address the mechanisms involved in eFSE-induced memory disorders and establish how such disorders can be reversed through genetic methods. These studies will also provide novel insights into mechanisms of memory-circuit maturation and have a potential major impact on a large population of children with febrile status epilepticus.